Nonsyndromic cleft palate: An association study at GWAS candidate loci in a multiethnic sample

Nina Ishorst, Paola Francheschelli, Anne C. Böhmer, Mohammad Faisal J. Khan, Stefanie Heilmann-Heimbach, Nadine Fricker, Julian Little, Regine P. M. Steegers-Theunissen, Borut Peterlin, Stefanie Nowak, Markus Martini, Teresa Kruse, Anton Dunsche, Thomas Kreusch, Lina Gölz, Khalid Aldhorae, Esam Halboub, Heiko Reutter, Peter Mossey, Markus M. NöthenMichele Rubini, Kerstin U. Ludwig, Michael Knapp, Elisabeth Mangold

Research output: Contribution to journalArticle

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Abstract

Background: Nonsyndromic cleft palate only (nsCPO) is a common and multifactorial form of orofacial clefting. In contrast to successes achieved for the other common form of orofacial clefting, that is, nonsyndromic cleft lip with/without cleft palate (nsCL/P), genome wide association studies (GWAS) of nsCPO have identified only one genome wide significant locus. Aim of the present study was to investigate whether common variants contribute to nsCPO and, if so, to identify novel risk loci.

Methods: We genotyped 33 SNPs at 27 candidate loci from 2 previously published nsCPO GWAS in an independent multiethnic sample. It included: (i) a family-based sample of European ancestry (n = 212); and (ii) two case/control samples of Central European (n = 94/339) and Arabian ancestry (n = 38/231), respectively. A separate association analysis was performed for each genotyped dataset, and meta-analyses were performed.

Results: After association analysis and meta-analyses, none of the 33 SNPs showed genome-wide significance. Two variants showed nominally significant association in the imputed GWAS dataset and exhibited a further decrease in p-value in a European and an overall meta-analysis including imputed GWAS data, respectively (rs395572: PMetaEU = 3.16 × 10-4; rs6809420: PMetaAll = 2.80 × 10-4).

Conclusion: Our findings suggest that there is a limited contribution of common variants to nsCPO. However, the individual effect sizes might be too small for detection of further associations in the present sample sizes. Rare variants may play a more substantial role in nsCPO than in nsCL/P, for which GWAS of smaller sample sizes have identified genome-wide significant loci. Whole-exome/genome sequencing studies of nsCPO are now warranted.

Original languageEnglish
Pages (from-to)871-882
Number of pages12
JournalBirth Defects Research
Volume110
Issue number10
Early online date2 Mar 2018
DOIs
Publication statusPublished - 1 Jun 2018

Fingerprint

Genome-Wide Association Study
Cleft Palate
Genes
Genome
Meta-Analysis
Cleft Lip
Sample Size
Single Nucleotide Polymorphism
Exome

Keywords

  • congenital malformation
  • nonsyndromic cleft palate only
  • common variants
  • imputed genome-wide association study
  • candidate loci
  • association study

Cite this

Ishorst, N., Francheschelli, P., Böhmer, A. C., Khan, M. F. J., Heilmann-Heimbach, S., Fricker, N., ... Mangold, E. (2018). Nonsyndromic cleft palate: An association study at GWAS candidate loci in a multiethnic sample. Birth Defects Research, 110(10), 871-882. https://doi.org/10.1002/bdr2.1213
Ishorst, Nina ; Francheschelli, Paola ; Böhmer, Anne C. ; Khan, Mohammad Faisal J. ; Heilmann-Heimbach, Stefanie ; Fricker, Nadine ; Little, Julian ; Steegers-Theunissen, Regine P. M. ; Peterlin, Borut ; Nowak, Stefanie ; Martini, Markus ; Kruse, Teresa ; Dunsche, Anton ; Kreusch, Thomas ; Gölz, Lina ; Aldhorae, Khalid ; Halboub, Esam ; Reutter, Heiko ; Mossey, Peter ; Nöthen, Markus M. ; Rubini, Michele ; Ludwig, Kerstin U. ; Knapp, Michael ; Mangold, Elisabeth. / Nonsyndromic cleft palate : An association study at GWAS candidate loci in a multiethnic sample. In: Birth Defects Research. 2018 ; Vol. 110, No. 10. pp. 871-882.
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title = "Nonsyndromic cleft palate: An association study at GWAS candidate loci in a multiethnic sample",
abstract = "Background: Nonsyndromic cleft palate only (nsCPO) is a common and multifactorial form of orofacial clefting. In contrast to successes achieved for the other common form of orofacial clefting, that is, nonsyndromic cleft lip with/without cleft palate (nsCL/P), genome wide association studies (GWAS) of nsCPO have identified only one genome wide significant locus. Aim of the present study was to investigate whether common variants contribute to nsCPO and, if so, to identify novel risk loci.Methods: We genotyped 33 SNPs at 27 candidate loci from 2 previously published nsCPO GWAS in an independent multiethnic sample. It included: (i) a family-based sample of European ancestry (n = 212); and (ii) two case/control samples of Central European (n = 94/339) and Arabian ancestry (n = 38/231), respectively. A separate association analysis was performed for each genotyped dataset, and meta-analyses were performed.Results: After association analysis and meta-analyses, none of the 33 SNPs showed genome-wide significance. Two variants showed nominally significant association in the imputed GWAS dataset and exhibited a further decrease in p-value in a European and an overall meta-analysis including imputed GWAS data, respectively (rs395572: PMetaEU = 3.16 × 10-4; rs6809420: PMetaAll = 2.80 × 10-4).Conclusion: Our findings suggest that there is a limited contribution of common variants to nsCPO. However, the individual effect sizes might be too small for detection of further associations in the present sample sizes. Rare variants may play a more substantial role in nsCPO than in nsCL/P, for which GWAS of smaller sample sizes have identified genome-wide significant loci. Whole-exome/genome sequencing studies of nsCPO are now warranted.",
keywords = "congenital malformation, nonsyndromic cleft palate only, common variants, imputed genome-wide association study, candidate loci, association study",
author = "Nina Ishorst and Paola Francheschelli and B{\"o}hmer, {Anne C.} and Khan, {Mohammad Faisal J.} and Stefanie Heilmann-Heimbach and Nadine Fricker and Julian Little and Steegers-Theunissen, {Regine P. M.} and Borut Peterlin and Stefanie Nowak and Markus Martini and Teresa Kruse and Anton Dunsche and Thomas Kreusch and Lina G{\"o}lz and Khalid Aldhorae and Esam Halboub and Heiko Reutter and Peter Mossey and N{\"o}then, {Markus M.} and Michele Rubini and Ludwig, {Kerstin U.} and Michael Knapp and Elisabeth Mangold",
note = "Funding: German Research Foundation . Grant Numbers: FOR 423 , MA 2546/3-1 , KR 1912/7-1 , NO 246/6-1 , WI 1555/5-1 , LU-1944/3-1; European Science Foundation . Grant Number: 09-RNP-023 (EMRC); ESF Network: EUROCleftNet.",
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Ishorst, N, Francheschelli, P, Böhmer, AC, Khan, MFJ, Heilmann-Heimbach, S, Fricker, N, Little, J, Steegers-Theunissen, RPM, Peterlin, B, Nowak, S, Martini, M, Kruse, T, Dunsche, A, Kreusch, T, Gölz, L, Aldhorae, K, Halboub, E, Reutter, H, Mossey, P, Nöthen, MM, Rubini, M, Ludwig, KU, Knapp, M & Mangold, E 2018, 'Nonsyndromic cleft palate: An association study at GWAS candidate loci in a multiethnic sample', Birth Defects Research, vol. 110, no. 10, pp. 871-882. https://doi.org/10.1002/bdr2.1213

Nonsyndromic cleft palate : An association study at GWAS candidate loci in a multiethnic sample. / Ishorst, Nina; Francheschelli, Paola; Böhmer, Anne C.; Khan, Mohammad Faisal J.; Heilmann-Heimbach, Stefanie; Fricker, Nadine; Little, Julian; Steegers-Theunissen, Regine P. M.; Peterlin, Borut; Nowak, Stefanie; Martini, Markus; Kruse, Teresa; Dunsche, Anton; Kreusch, Thomas; Gölz, Lina; Aldhorae, Khalid; Halboub, Esam; Reutter, Heiko; Mossey, Peter; Nöthen, Markus M.; Rubini, Michele; Ludwig, Kerstin U.; Knapp, Michael; Mangold, Elisabeth (Lead / Corresponding author).

In: Birth Defects Research, Vol. 110, No. 10, 01.06.2018, p. 871-882.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Nonsyndromic cleft palate

T2 - An association study at GWAS candidate loci in a multiethnic sample

AU - Ishorst, Nina

AU - Francheschelli, Paola

AU - Böhmer, Anne C.

AU - Khan, Mohammad Faisal J.

AU - Heilmann-Heimbach, Stefanie

AU - Fricker, Nadine

AU - Little, Julian

AU - Steegers-Theunissen, Regine P. M.

AU - Peterlin, Borut

AU - Nowak, Stefanie

AU - Martini, Markus

AU - Kruse, Teresa

AU - Dunsche, Anton

AU - Kreusch, Thomas

AU - Gölz, Lina

AU - Aldhorae, Khalid

AU - Halboub, Esam

AU - Reutter, Heiko

AU - Mossey, Peter

AU - Nöthen, Markus M.

AU - Rubini, Michele

AU - Ludwig, Kerstin U.

AU - Knapp, Michael

AU - Mangold, Elisabeth

N1 - Funding: German Research Foundation . Grant Numbers: FOR 423 , MA 2546/3-1 , KR 1912/7-1 , NO 246/6-1 , WI 1555/5-1 , LU-1944/3-1; European Science Foundation . Grant Number: 09-RNP-023 (EMRC); ESF Network: EUROCleftNet.

PY - 2018/6/1

Y1 - 2018/6/1

N2 - Background: Nonsyndromic cleft palate only (nsCPO) is a common and multifactorial form of orofacial clefting. In contrast to successes achieved for the other common form of orofacial clefting, that is, nonsyndromic cleft lip with/without cleft palate (nsCL/P), genome wide association studies (GWAS) of nsCPO have identified only one genome wide significant locus. Aim of the present study was to investigate whether common variants contribute to nsCPO and, if so, to identify novel risk loci.Methods: We genotyped 33 SNPs at 27 candidate loci from 2 previously published nsCPO GWAS in an independent multiethnic sample. It included: (i) a family-based sample of European ancestry (n = 212); and (ii) two case/control samples of Central European (n = 94/339) and Arabian ancestry (n = 38/231), respectively. A separate association analysis was performed for each genotyped dataset, and meta-analyses were performed.Results: After association analysis and meta-analyses, none of the 33 SNPs showed genome-wide significance. Two variants showed nominally significant association in the imputed GWAS dataset and exhibited a further decrease in p-value in a European and an overall meta-analysis including imputed GWAS data, respectively (rs395572: PMetaEU = 3.16 × 10-4; rs6809420: PMetaAll = 2.80 × 10-4).Conclusion: Our findings suggest that there is a limited contribution of common variants to nsCPO. However, the individual effect sizes might be too small for detection of further associations in the present sample sizes. Rare variants may play a more substantial role in nsCPO than in nsCL/P, for which GWAS of smaller sample sizes have identified genome-wide significant loci. Whole-exome/genome sequencing studies of nsCPO are now warranted.

AB - Background: Nonsyndromic cleft palate only (nsCPO) is a common and multifactorial form of orofacial clefting. In contrast to successes achieved for the other common form of orofacial clefting, that is, nonsyndromic cleft lip with/without cleft palate (nsCL/P), genome wide association studies (GWAS) of nsCPO have identified only one genome wide significant locus. Aim of the present study was to investigate whether common variants contribute to nsCPO and, if so, to identify novel risk loci.Methods: We genotyped 33 SNPs at 27 candidate loci from 2 previously published nsCPO GWAS in an independent multiethnic sample. It included: (i) a family-based sample of European ancestry (n = 212); and (ii) two case/control samples of Central European (n = 94/339) and Arabian ancestry (n = 38/231), respectively. A separate association analysis was performed for each genotyped dataset, and meta-analyses were performed.Results: After association analysis and meta-analyses, none of the 33 SNPs showed genome-wide significance. Two variants showed nominally significant association in the imputed GWAS dataset and exhibited a further decrease in p-value in a European and an overall meta-analysis including imputed GWAS data, respectively (rs395572: PMetaEU = 3.16 × 10-4; rs6809420: PMetaAll = 2.80 × 10-4).Conclusion: Our findings suggest that there is a limited contribution of common variants to nsCPO. However, the individual effect sizes might be too small for detection of further associations in the present sample sizes. Rare variants may play a more substantial role in nsCPO than in nsCL/P, for which GWAS of smaller sample sizes have identified genome-wide significant loci. Whole-exome/genome sequencing studies of nsCPO are now warranted.

KW - congenital malformation

KW - nonsyndromic cleft palate only

KW - common variants

KW - imputed genome-wide association study

KW - candidate loci

KW - association study

U2 - 10.1002/bdr2.1213

DO - 10.1002/bdr2.1213

M3 - Article

C2 - 29498243

VL - 110

SP - 871

EP - 882

JO - Birth Defects Research

JF - Birth Defects Research

SN - 2472-1727

IS - 10

ER -

Ishorst N, Francheschelli P, Böhmer AC, Khan MFJ, Heilmann-Heimbach S, Fricker N et al. Nonsyndromic cleft palate: An association study at GWAS candidate loci in a multiethnic sample. Birth Defects Research. 2018 Jun 1;110(10):871-882. https://doi.org/10.1002/bdr2.1213